Transmucosal formulations of levosimendan

ABSTRACT

A method of administering transmucosally, particularly to oral or nasal mucosa, levosimendan or a pharmaceutically acceptable salt thereof to a patient. The method comprises contacting an intact mucous membrane with a source of levosimendan, and maintaining said source with said mucous membrane for a sufficient time period to deliver levosimendan to the patient. Transmucosal preparations of levosimendan are also described. Levosimendan is useful in the treatment of heart failure.

This application is a national stage filing of PCT InternationalApplication No. PCT/FI98/00977, filed Dec. 11, 1998, the content ofwhich is incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to transmucosal delivery of levosimendanor a pharmaceutically acceptable salt thereof, particularly delivery viaoral and nasal mucosa. The invention also relates to transmucosal,particularly intraoral and intranasal, e.g. buccal, sublingual orsinuidal, preparations comprising levosimendan or a pharmaceuticallyacceptable salt thereof as the active ingredient.

Levosimendan, which is the (-)-enantiomer of[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile(I), and the method for its preparation is described e.g. in EP 565546B1. Levosimendan is potent in the treatment of heart failure and hassignificant calcium dependent binding to troponin. The use oflevosimendan in the treatment of myocardial ischemia is described in WO93/21921. Pharmacokinetics of levosimendan in man after i.v. and oraldosing is described in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol.,26(Suppl. 1), S57-S62, 1995.

Clinical studies have confirmed the beneficial effects of levosimendanin heart failure patients.

SUMMARY OF THE INVENTION

It has now been found that therapeutically effective and steady serumlevels of levosimendan are rapidly achieved by administeringlevosimendan transmucosally, preferably to oral or nasal mucosa.Furthermore, it has been found that by administering levosimendantransmucosally the occurence of undesired side effects such as headacheand palpitation connected to the oral administration of levosimendan canbe reduced or totally avoided. It is now believed that activemetabolites formed in the gastrointestinal tract by intestinal bacteriacontribute to the observed undesired effects. The formation ofmetabolites in the gastrointestinal tract can be reduced or totallyavoided by transmucosal administration.

Accordingly, the object of the invention is to provide a method foradministering transmucosally, i.e. to and across a mucosal surface,levosimendan or a pharmaceutically acceptable salt thereof. The mucosalsurface is preferably oral or nasal mucosa such as the buccal mucosa,the sublingual mucosa, the sinuidal mucosa, the gum, or the inner lip.

The present invention also provides transmucosal, particularly intraoraland intranasal, e.g. buccal, sublingual or sinuidal, preparationscomprising levosimendan or a pharmaceutically acceptable salt thereof asa therapeutically active ingredient.

The present invention also provides the use of levosimendan or apharmaceutically acceptable salt there6f in the manufacture of amedicament for transmucosal administration, particularly to oral andnasal mucosa, of levosimendan or a pharmaceutically acceptable saltthereof.

Furthermore the present invention provides a method for treating heartfailure comprising administering transmucosally, particularly to oraland nasal mucosa, a therapeutically effective amount of levosimendan ora pharmaceutically acceptable salt thereof to a subject in need of suchtreatment.

Furthermore the present invention provides a method of administeringtransmucosally, particularly to oral and nasal mucosa, levosimendan or apharmaceutically acceptable salt thereof to a patient, wherein themethod comprises contacting an intact mucous membrane with a source oflevosimendan or a pharmaceutically acceptable salt thereof, andmaintaining said source in contact with said mucous membrane for asufficient time period to deliver said levosimendan or apharmaceutically acceptable salt thereof to the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the in vitro release of levosimendan from differentmucoadhesive buccal preparations.

DETAILED DESCRIPTION OF THE INVENTION

The transmucosal administration of levosimendan or a pharmaceuticallyacceptable salt thereof can be accomplished generally by contacting anintact mucous membrane with a source of levosimendan or apharmaceutically acceptable salt thereof, and maintaining said source incontact with said mucous membrane for a sufficient time period to inducethe desired therapeutic effect. Preferably the drug is administered tooral or nasal mucosa such as the buccal mucosa, the sublingual mucosa,the sinuidal mucosa, the gum, or the inner lip.

The precise amount of the drug administered according to the inventionis dependent on numerous factors, such as age and body weight of thepatient, the condition of the patient and the desired duration of use.The daily dose of levosimendan to human patients is within the range ofabout 0.1 to 500 mg, preferably 0.5 to 10 mg. The blood concentration oflevosimendan in human patients can be about 1-300 ng/ml, preferably10-150 ng/ml, especially 20-60 ng/ml. The time period for administeringlevosimendan from a sustained release preparation such as antransmucosal patch is from about 4 to 24 hours, typically about 12hours.

The source of the drug can be any transmucosal preparation suitable foradministering levosimendan or a pharmaceutically acceptable saltthereof. Particularly, the source of the drug is any preparation usablein oral, nasal, sinuidal or vaginal cavities that can be formulatedusing conventional techniques well known in the art. Preferredpreparations are those usable in oral or nasal cavities. For example,the preparation can be a buccal tablet, a sublingual tablet, a spray,and the like preparation that dissolve or disintegrate, delivering druginto the mouth of the patient. A spray or drops can be used to deliverthe drug to nasal or sinuidal cavities. Said preparation may or may notdeliver the drug in a sustained fashion. The manufacture examples forsuch preparations are disclosed for example in U.S. Pat. No. 4,764,378.

Suitably the source of the drug is a mucoadhesive preparation. A.mucoahdesive preparation is a preparation which upon contact with intactmucous membrane adheres to said mucous membrane for a sufficient timeperiod to induce the desired therapeutic effect. The preparation can bea semisolid composition as described e.g. in WO 96/09829. It can be atablet, a powder, a gel or film comprising a mucoadhesive matrix asdescribed e.g. in WO 96/30013. The preparation can also be a syrup thatadheres to the mucous membrane.

Suitable mucoadhesives include those well known in the art such aspolyacrylic acids, preferably having the molecular weight between fromabout 450,000 to about 4,000,000, e.g. Carbopol™ 934P; sodiumcarboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC),e.g. Methocel™ K100, and hydroxypropylcellulose.

The preparation can also be in the form of a bandage, patch, device andthe like preparation that contains the drug and adheres to a mucosalsurface. Suitable transmucosal patches are described for example in WO93/23011. A suitable patch may comprise a backing. The backing can beany flexible film that prevents bulk fluid flow and provides a barrierfor to loss of the drug from the patch. The backing can be any of theconventional materials such as polyethylene, ethyl-vinyl acetatecopolymer, polyurethane and the like. In a patch involving a matrixwhich is not itself a mucoadhesive, the drug-containing matrix can becoupled with a mucoadhesive component (such as a mucoadhesive describedabove) in order that the patch may be retained on the mucosal surface.Suitable configurations include a patch or device wherein the matrix hasa smaller periphery than the backing layer such that a portion of thebacking layer extends outward from the periphery of the matrix. Amucoadhesive layer covers the outward extending portion of the backinglayer such that the underside of the backing layer carries a layer ofmucoadhesive around its periphery. The backing and the peripheral ringof mucoadhesive taken together form a reservoir which contains adrug-containing matrix (e.g. a tablet, gel, or powder). It may bedesirable to incorporate a barrier element between the matrix and themucoadhesive in order to isolate the mucoadhesive from the matrix. Thebarrier element is preferably substantially impermeable to water and tothe mucosal fluids that will be present at intended site of adhesion. Apatch or device having such barrier element can be hydrated only througha surface that is in contact with the mucosa, and it is not hydrated viathe reservoir. Such patches can be prepared by general methods wellknown to those skilled in the art.

Preparations usable according to the invention can containpharmaceutical ingredients, such as fillers, lubricants, disintegrants,solubilizing vehicles, flavours, dyes and the like. It may be desirablein some instances to incorporate a mucous membrane penetration enhancerinto the preparation. Suitable penetration enhancers include anionicsurfactants (e.g. sodium lauryl sulphate, sodium dodecyl sulphate),cationic surfactants (e.g. palmitoyl DL camitine chloride,cetylpyridinium chloride), nonionic surfactants (e.g. polysorbate 80,polyoxyethylene 9-lauryl ether, glyceryl monolaurate, polyoxyalkylenes,polyoxyethylene 20 cetyl ether), lipids (e.g. oleic acid), bile salts(e.g. sodium glycocholate, sodium taurocholate),and related compounds.

The invention will be further clarified by the following examples, whichare intended to be purely exemplary of the invention.

EXAMPLES Example 1

Bioavailability of Levosimendan Following Buccal and IntravenousAdministration in Dogs.

Bioavailability of levosimendan was studied in dogs following buccal andintravenous administration of 0.02 mg/kg of the compound. Asexperimental animals, three beagle dogs were used. At the time of dosingall animals weighed approximately 10 kg. The dogs were givenlevosimendan as an intravenous injection or buccal spray at one weekintervals. Appropriate concentration (2 mg/ml in 96% ethanol) of thecompound was prepared in 10 ml amber glass containers sealed with spraynozzles (50 μl dose, Pfeiffer). The 0.02 mg/kg buccal dose was thusobtained by spraying 2 consecutive 50 μl doses to the buccal cavity ofthe animals (the dosing volume being thus 0.1 ml/10 kg). The iv dose(0.1 ml/10 kg) was taken from the same bottles.

5 ml of blood was collected from the cephalic vein at the followingtimes after administration: 0, 10, 20, 40, min, 1, 1.5 and 2 hours.Plasma was separated and stored frozen in −20 ° C. until analyzed.

Determination of Levosimendan in Dog Plasma

Levosimendan in dog plasma was determined by a non-enantioselectivemethod, in which an automated sample preparation technique combined withhigh performance liquid chromatography was used. The plasma clean-up wasperformed by on-line dialysis and the, dialysate was retained on a traceenrichment column. The analyte was then-separated on an analyticalcolumn and detected with a UV-detector. The limit of quantitation was 5ng/ml and the quantitation range 5-500 ng/ml.

The apparatus comprised a Gilson ASTED (Automated Sequential TraceEnrichment System) system (Gilson Medical Electronics, Villiers-le-Bel,France). The dialysis cell was fitted with a Cuprophan cellulosemembrane with a molecular cut-off of 15 kDa and the trace enrichmentcolumn was a Hypersil ODS (5.8×4.6 mm i.d., 10 μm). The chromatographicsystem consisted of an LKB Model 2150 pump (Bromma, Sweden) and aLichrosorb RP-18 (250×4 mm i.d., 10 μm) column (Merck, Darmstadt,Germany). The detector was a Spectra 100 UV-VIS (Spectra-Physics, SanJose, Calif., USA). The wavelength was 380 nm. The mobile phaseconsisted of a 32 mM monosodium dihydrogen phosphate buffer, methanol,and tetrahydrofuran (45:65:1, v/v/v, pH 3.5). The mobile phase flow ratewas 1.0 ml/min.

The results are shown in table 1.

TABLE 1. Levosimendan concentrations in dog plasma after buccal andintravenous (iv) administration. Levosimendan concentration (ng/ml) Time(min) Dog 1 Dog 2 Dog 3 Buccal:  0 < < < 10 10 17 7.6 20 24 24 9.4 40 3225 25 60 26 22 24 90 18 17 22 120  13 12 16 iv:  0 < < < 10 128  103 100 20 105  71 82 40 74 46 58 60 58 36 46 90 39 24 33 120  28 15 25 <means below quantitation range

Table 1 shows that levosimendan is rapidly absorbed into blood from thebuccal spray and steady serum levels of levosimendan are obtained.

Example 2

Preparation of Mucoadhesive Buccal Tablets and in Vitro ReleaseExperiment

Five different mucoadhesive buccal tablet formulations of levosimendanwere prepared according to Table 2.

TABLE 2. Five different mucoadhesive buccal tablet formulations oflevosimendan Amount (mg) Constituent I II III IV V Levosimendan 2 2 2 22 HPMC K100 78 42.9 70.2 62.4 70.2 Lactose — 31.2 — — — Carbopol ™ 934P— 3.9 — — — NaCMC ulv — — 7.8 15.6 — NaCMC lv — — — — 7.8 ulv = ultralow viscosity lv = low viscosity

Buccal tablets described above were prepared by mixing powders neededfor a batch of desired size in Turbula mixer and pressing in a tabletpress using 7 mm punchs and 5-8 kN compression force. The thickness ofthe tablets was about 1.8 mm.

The release of levosimendan from the preparations was studied using thepaddle method according to USP XXII. The dissolution medium wasphosphate buffer pH 5.8. The rotation speed of the paddles 50 rpm.

FIG.1 shows the release (%) of levosimendan vs. time (h) from the buccaltablets of Table 2. All preparations acted as long-acting preparations.Preparations I, II, III and V released levosimendan according to zeroorder kinetics up to 10 hours. The addition of NaCMC increased therelease of levosimendan from buccal tablets. The figure shows that theposition of the release curve may be systematically adjusted with theaid of amount and type of the mucoadhesive polymer. The legends in FIG.1mean

Δ formulation I

▪ formulation II

□ formulation III

∇ formulation IV

▴ formulation V

What is claimed is:
 1. A transmucosal preparation comprisinglevosimendan or a pharmaceutically acceptable salt thereof as atherapeutically active ingredient, together with one or morepharmaceutically acceptable excipients.
 2. A preparation according toclaim 1 which upon contact with intact mucous membrane adheres to saidmucous membrane for a sufficient time period to induce the desiredtherapeutic effect.
 3. A preparation according to claim 1, which is inthe form of a mucoadhesive preparation.
 4. A preparation according toclaim 1, which comprises a mucoadhesive matrix.
 5. A preparationaccording to claim 1, which is in the form of a patch.
 6. A method fortreating heart failure comprising administering transmucosally atherapeutically effective amount of levosimendan or a pharmaceuticallyacceptable salt thereof to a subject in need of such treatment.
 7. Amethod of administering levosimendan or a pharmaceutically acceptablesalt thereof transmucosally to a patient, which comprises contacting anintact mucous membrane of the patient with a source of levosimendan or apharmaceutically acceptable salt thereof, and maintaining said source incontact with said mucous membrane for a sufficient time period todeliver said levosimendan or a pharmaceutically acceptable salt thereofto the patient.
 8. A method as claimed in claim 6, wherein thelevosimendan or pharmaceutically acceptable salt thereof is administeredto the oral or nasal mucosa.
 9. A method as claimed in claim 7, whereinthe intact mucous membrane is an oral or nasal mucous membrane.